The clinical development of FLT3 inhibitors in acute myeloid leukemia

Knapper, Steven ORCID: https://orcid.org/0000-0002-6405-4441 2011. The clinical development of FLT3 inhibitors in acute myeloid leukemia. Expert Opinion on Investigational Drugs 20 (10) , pp. 1377-1395. 10.1517/13543784.2011.611802

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Abstract

Introduction: Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur at high frequency in acute myeloid leukemia (AML), being detected in > 30% of patients at diagnosis and carrying a profound negative prognostic impact. The development of effective small molecule inhibitors of FLT3 has been the focus of an intensive international research effort in recent years. Areas covered: The published results of the first decade of clinical trials of FLT3-targeted tyrosine kinase inhibitors are critically reviewed. Over this period, a first generation of compounds has followed an orderly progression from monotherapy studies through combination with chemotherapy and into advanced stage international trials in both relapsed and newly-diagnosed AML. Correlative laboratory studies performed alongside several of these studies have been highly illuminating, demonstrating close correlations between clinical activity and effective inhibition of FLT3, and highlighting potential drug resistance mechanisms. Expert opinion: Clinical responses to several of the early multi-targeted agents were hindered by unfavorable pharmacokinetics and lack of potency. Newer, more potent FLT3 inhibitors such as sorafenib and AC220 possess the ability to achieve more sustained in vivo inhibition of FLT3 and have shown highly promising activity in early clinical studies. As these agents enter advanced stage trials, they carry the potential to make a major clinical impact in this disease. In future, FLT3 inhibitors may be effectively used in combination with other molecularly targeted agents.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	AC220, acute myeloid leukemia, CEP701, FLT3, inhibitor, kinase, lestaurtinib, midostaurin, PKC412, sorafenib, tyrosine
Publisher:	Informa Healthcare
ISSN:	1354-3784
Last Modified:	20 Oct 2022 08:34
URI:	https://orca.cardiff.ac.uk/id/eprint/28820

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